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Genetics and epigenetics of fetal alcohol spectrum disorders

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195732 Year: Pages: 114 DOI: 10.3389/978-2-88919-573-2 Language: English
Publisher: Frontiers Media SA
Subject: Biology --- Science (General) --- Genetics
Added to DOAB on : 2016-02-05 17:24:33
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Women drinking during pregnancy can result in Fetal Alcohol Spectrum Disorder (FASD), which may feature variable neurodevelopmental deficits, facial dysmorphology, growth retardation, and learning disabilities. Research suggests the human brain is precisely formed through an intrinsic, genetic-cellular expression that is carefully orchestrated by an epigenetic program. This program can be influenced by environmental inputs such as alcohol. Current research suggests the genetic and epigenetic elements of FASD are heavily intertwined and highly dependent on one another. As such, now is the time for investigators to combine genetic, genomic and epigenetic components of alcohol research into a centralized, accessible platform for discussion. Genetic analyses inform gene sets which may be vulnerable to alcohol exposure during early neurulation. Prenatal alcohol exposure indeed alters expression of gene subsets, including genes involved in neural specification, hematopoiesis, methylation, chromatin remodeling, histone variants, eye and heart development. Recently, quantitative genomic mapping has revealed loci (QTLs) that mediate alcohol-induced phenotypes identified between two alcohol-drinking mouse strains. One question to consider is (besides the role of dose and stage of alcohol exposure) why only 5% of drinking women deliver newborns diagnosed with FAS (Fetal Alcohol Syndrome)? Studies are ongoing to answer this question by characterizing genome-wide expression, allele-specific expression (ASE), gene polymorphisms (SNPs) and maternal genetic factors that influence alcohol vulnerability. Alcohol exposure during pregnancy, which can lead to FASD, has been used as a model to resolve the epigenetic pathway between environment and phenotype. Epigenetic mechanisms modify genetic outputs through alteration of 3D chromatin structure and accessibility of transcriptional machinery. Several laboratories have reported altered epigenetics, including DNA methylation and histone modification, in multiple models of FASD. During development DNA methylation is dynamic yet orchestrated in a precise spatiotemporal manner during neurulation and coincidental with neural differentiation. Alcohol can directly influence epigenetics through alterations of the methionine pathway and subsequent DNA or histone methylation/acetylation. Alcohol also alters noncoding RNA including miRNA and transposable elements (TEs). Evidence suggests that miRNA expression may mediate ethanol teratology, and TEs may be affected by alcohol through the alteration of DNA methylation at its regulatory region. In this manner, the epigenetic and genetic components of FASD are revealing themselves to be mechanistically intertwined. Can alcohol-induced epigenomic alterations be passed across generations? Early epidemiological studies have revealed infants with FASD-like features in the absence of maternal alcohol, where the fathers were alcoholics. Novel mechanisms for alcohol-induced phenotypes include altered sperm DNA methylation, hypomethylated paternal allele and heritable epimutations. These studies predict the heritability of alcohol-induced epigenetic abnormalities and gene functionality across generations. We opened a forum to researchers and investigators the field of FASD to discuss their insights, hypotheses, fresh data, past research, and future research themes embedded in this rising field of the genetics and epigenetics of FASD. This eBook is a product of the collective sharing and debate among researchers who have contributed or reviewed each subject.

All 3 Types of Glial Cells Are Important for Memory Formation

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450251 Year: Pages: 150 DOI: 10.3389/978-2-88945-025-1 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2018-02-27 16:16:44
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The vertebrate brain contains neurons and 3 classical types of glia cells, astrocytes, oligodendrocytes and microglia. Astrocytes and microglia have mainly been studied in gray matter, whereas oligodendrocytes myelinate white matter tracts. Until recently microglial effects were considered mainly during pathological conditions, but is now known that microglia plays important roles also in normal brain function. All these 3 glial cell types and their collaboration with neurons are important for learning. The concept that glia cells are important for cognitive function is not new. A glial-neuronal theory of brain function was proposed by Galambos in 1961. Hyden and Egyhazi demonstrated glial RNA changes in microdissected glia cells during learning in rats in 1963, and astrocytic and oligodendrocytic involvement of K+-mediated effects of learning has been suggested and/or demonstrated from the 1960’s and onwards as recently reviewed by Hertz and Chen (Neuroscience and Biobehavioural Reviews, 2016). In 1969 van den Berg et al. showed compartmentation of glutamate in brain and thus of production of the neurotransmitters glutamate and GABA, which are essential for learning. That glutamate is synthesized in astrocytes because they in contrast to neurons express the enzyme pyruvate carboxylase was demonstrated 10-15 years later by Yu et al. in cultured astrocytes and Shank et al. in intact brain tissue. However, the present e-book focuses on more recent developments. Most information is available about astrocytic roles in learning. The importance of astrocytes in the tripartite synapse and of microglia in the tetrapartite synapse is illustrated in the front-page figure, which emphasizes the role of gliotransmitters and of Ca2+ transport through gap junctions, coupling astrocytes into a functional syncytium. Astrocytes are important for establishments of brain rhythms, which may differ in different cognitive tasks, and although the exact reason why knock-out of the astrocytic water channel AQP4 impairs memory remains to be established, several possibilities are discussed. The importance of the two astrocyte specific processes glutamate and glutamine formation and glycogenolysis is discussed in considerable detail. Glycogenolysis is important not only for astrocytic processes involved in learning, but also for those in neurons because glycolytically derived lactate has signaling functions in the extracellular space and may be accumulated in minute quantities into very specific and small neuronal structures. Some neurotransmitters stimulating glycogenolysis are also involved in psychiatric disease. Noradrenaline, released from locus coeruleus exerts direct effects on both astrocytes and neurons and in addition promotes secretion of corticotropin-releasing hormone and adrenocorticotrophic hormone (ACTH) in brain, and of glucocorticoids from the adrenal cortex, all of which are responsible for stress effects on learning. Lead causes memory impairment by inhibition of glutamine formation due to oxidative stress and reduced effectiveness of the glutathione system. The many adverse effects of fetal alcohol exposure on behaviour and learning are caused by a multitude of effects on all three types of glia cells. Traumatic brain injury also exerts multifactorial effects, including microglia/astrocyte-induced secretion of neuroinflammatory molecules and axonal disruption and oligodendrocytic dysfunction. In normal brain oligodendrocytes respond to the depolarization caused by neuronal activity with accelerated conduction velocity and increased compound action potentials which facilitate learning.

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